Natural killer (NK) cell defects, commonly seen in metastatic breast cancer (MBC) lead to decrease in dendritic cell (DC) maturation, proinflammatory cytokine production, and tumor infiltrating T-cells (TILs). This results in a protumorigenic Th2 immune microenvironment with low response rates to immunotherapy (i.e., immune checkpoint blockade) and standard chemotherapy. PSK, a potent TLR-2 agonist, activates NK cells to produce IFN-γ and IL-12 and promote DC maturation/differentiation toward a Th1 profile in the tumor microenvironment which results in antigen specific TIL that can eradicate tumor. The combination immunotherapy of PSK and HER2 directed therapy described here, aims at inducing Th1 immunity and tumor specific T-cells. This proposed regimen could eradicate microscopic residual disease and prevent recurrence in optimally treated HER2+ MBC patients. Moreover, the regimen could result in enhanced trafficking of TILs to the site of tumor and improve the efficacy of checkpoint inhibitors and other therapies. A phase I/II randomized 2 arm study of combination immunotherapy with oral PSK (or placebo) given with a HER2 peptide vaccine and HER2 mAb therapy (trastuzumab (TZ) +/- pertuzumab (PZ)) was initiated to assess the safety of the approach and evaluate the effect of PSK on NK cell activity, pro-inflammatory cytokine/chemokine profile; and HER2 vaccine-induced T cell immunity.

Methods: Up to 30 patients with HER2+ MBC who are without evidence of disease after definitive therapy and currently on maintenance TZ +/- PZ are enrolled and randomly assigned in equal numbers to 1 of 2 arms (15 patients/arm): Arm 1: HER2 ICD vaccine + placebo or Arm 2: HER2 ICD vaccine + PSK. All patients receive concomitant treatment with 4 months of daily oral PSK or placebo, 3 monthly intradermal HER2 ICD vaccinations and continued TZ +/- PZ. Toxicity is evaluated per CTEP CTCAE 4.0, during and post vaccination. Serial blood draws for immunologic evaluation of NK cell activity and antigen-specific T cell immunity via flow cytometry and IFN-γ ELISPOT, respectively; and pro-inflammatory cytokines/chemokines.

Results: 24 subjects have been enrolled and 60 vaccines have been given. 16 subjects have completed all 3 vaccines and PSK/placebo; and 6 subjects are currently in progress. 2 subjects received < 3 vaccines and were taken off study. Of 144 reported adverse events (AEs), 97% were Grade 1-2; 66 (46%) were possibly, probably, or definitely related to study treatment. Most common AEs are injection site reaction and flu-like symptoms. There have been a total of four Grade 3 AEs, 1 episode of self-limited nausea/vomiting attributed to study treatment; and cognitive disturbance, fatigue, and lymphopenia all in 1 subject and attributed to disease progression. There have been no Grade 4 AEs. Immunologic analyses are ongoing and will be presented along with completed clinical data on all patients.

Conclusion: Combination immunotherapy with PSK/placebo and concurrent HER2 directed therapy is safe and well-tolerated. Further ongoing immunologic studies will help define the immunogenicity of the approach.

Citation Format: Salazar LG, Higgins D, Childs J, Coveler AL, Liao J, Stanton S, Gooley T, Standish LJ, Sasagawa M, DISIS ML. Phase I/II randomized study of combination immunotherapy with or without polysaccharide krestin (PSK) concurrently with a HER2 ICD peptide-based vaccine in patients with stage IV breast cancer receiving HER2-targeted monoclonal antibody therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-03.